Throughout this application various publications are referred to in parentheses. Full citations for these references may be found at the end of the specification. The disclosures of these publications, and all patents, patent application publications and books referred to herein, are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
The B7 and CD 28 families are part of the immune system. The B7 ligand family binds to the CD28 receptor family on T cells and other immune cells, which critically regulates functions of immune cells. The currently known members of the B7 family include B7-1 (CD80), B7-2 (CD86), B7h (CD275), PD-L1 (B7-H1, CD274), PD-L2 (B7-DC, CD273), B7-H3 (CD276), B7x (B7-H4/B7s1) and HHLA2, whereas the CD28 family contains CD28, CTLA-4 (CD152), ICOS (CD278) and PD-1 (CD279)(1-3). The B7/CD28 pathways are very attractive therapeutic targets (3-9). The FDA has approved five new drugs developed from the B7/CD28 families.
HHLA2 has recently been characterized as a member of the B7 family. In 2013, by homology search of various databases using amino acid sequences of human B7x and B7-H3, HERV-H LTR-associating 2 (HHLA2) was identified as a new member of the B7 family (1). The human HHLA2 gene is located in the q13.13 region of the chromosome 3 and is near the B7-1 and B7-2 genes (q13.3-q21). HHLA2 shares varying levels of amino acid similarity with human B7-1 (23%), B7-2 (29%), B7h (30%), PD-L1 (26%), PD-L2 (27%), B7-H3 long form (32%) and short form (33%), and B7x (30%) (1), which are comparable to the homologies exhibited by other members of the family; for example, B7-1, the founding member of the B7 family, shares 22-37% amino acid similarity with other human B7 molecules. HHLA2 protein is expressed on the cell surface and inhibits both human CD4 and CD8 T cell functions (1).
HHLA2 is widely expressed in many human cancers. It was recently shown that HHLA2 protein can be detected in the epithelium of the placenta, gut, kidney, gallbladder and breast, but not in most other organs (10). In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, esophagus and hematological malignancies of leukemia and lymphoma (10). A more detailed analysis was performed on a cohort of 50 patients with triple-negative breast cancer; 56% of patients had aberrant expression of HHLA2 on their tumors. This expression significantly correlated with advanced breast cancer stage and metastatic spread to lymph nodes (10). These results demonstrate that the endogenous HHLA2 protein is absent in most normal tissues, but is widely over-expressed in human cancers. Therefore the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and is an attractive target for human cancer therapy.
The present invention addresses the need for improved therapies and therapeutics based on the HERV-H LTR Associating Protein 2 (HHLA2) pathway based on identifying a binding partner protein for HHLA2.